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Advances in Brief |
Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263 [M. E. R., M. Y., E. C. T., J. L. S.], and Department of Biochemistry, Stanford University, Stanford, California 94305 [D. T. R.]
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ABSTRACT |
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(PML-RAR). The
purpose of this study was to identify genes that are regulated in a
PML-RAR-dependent fashion by retinoic acid (RA), because such genes
may be integrally involved in APL pathogenesis and/or myeloid
differentiation. A cDNA microarray approach was used to identify genes
induced in response to RA in TF1 myeloid leukemia cells expressing
PML-RAR (TF1-PR cells). The B94 gene (TNFAIP2; Unigene
Hs.101382), originally identified as a tumor necrosis factor
-inducible gene in endothelial cells, was one of several genes found
to be induced by RA specifically in TF1-PR cells, but not in TF1-neo
(control) cells. The induction of B94 was most pronounced in cells
expressing the PML-RAR short isoform and was negligible in cells
that expressed a mutant PML-RAR protein containing a deletion of the
PML coiled-coil domain. B94 induction by RA occurred within 1 h,
did not require new protein synthesis, and was inhibited by actinomycin
D, suggesting rapid transcriptional activation. B94 was also induced by
RA in NB4, UF1, and HL-60 cells, but not in other hematopoietic cell
lines tested, suggesting that its up-regulation by RA may be specific
to cells that express PML-RAR or are at the late myeloblast or
promyelocyte stage of myeloid development. A screen of bone marrow
cells from normal donors or patients with acute myelogenous leukemia
showed that B94 was highly expressed in normal marrow and in marrow
from patients with acute myelogenous leukemia French-American-British
subtypes M0-M2, but was repressed in marrow
cells from APL patients. Treatment of APL blasts in vitro
with all-trans-RA resulted in up-regulation of B94 mRNA.
These results suggest that B94 plays a role in myeloid development and
support the hypothesis that B94 is a target gene of PML-RAR in APL. |
Introduction |
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, plays both causative and curative roles
in this disease: in the absence of ATRA, it blocks transcription of
genes required for myeloid differentiation, whereas in the presence of
ATRA, it appears to facilitate expression of such genes, leading to
differentiation and perhaps to apoptosis of leukemic cells (1
, 2)
. One approach to understanding the role of PML-RAR in APL
is to identify genes that are transcriptionally repressed by this
molecule and induced by ATRA specifically (or preferentially) in
PML-RAR-positive cells.
Several lines of evidence suggest that PML-RAR inhibits myeloid
differentiation by interfering with transcriptional activation of RA
target genes (4
, 5)
. RAR/retinoid X receptor heterodimers
bind RA target gene promoters in association with nuclear receptor
corepressors (Silencing mediator for retinoid and thyroid hormone
receptors or nuclear receptor corepressor and mSin3A) and HDACs.
Histone deacetylation yields a chromatin conformation unfavorable for
transcription; however, the binding of RA to its cognate receptor
results in dissociation of the N-CoR complex and restoration of a
transcriptionally active chromatin structure. Compared with native
RAR, the PML-RAR-corepressor interaction is far less sensitive to
RA, resulting in histone deacetylation and transcriptional repression
even in the presence of physiological concentrations of RA. The ability
of pharmacological doses of RA to dissociate the PML-RAR-corepressor
complex underlies the current approach to APL treatment and is felt to
restore expression of genes involved in myeloid differentiation
(4
, 6 , 7)
. Identification of these RA target genes is an
important avenue of future research in APL, and several candidate genes
have been identified (8
, 9)
.
B94 is a cytokine-inducible immediate early gene that was originally
identified as a TNF--inducible transcript in human endothelial cells
(10)
. Developmental studies in the mouse indicate that B94
mRNA is expressed in hematopoietic and lymphoid tissues
(11)
, suggesting that B94 plays a role in blood cell
development. Two recent genome-wide screens have identified B94
transcripts in microglial cells (12)
, postulated to arise
from the monocytic lineage, and in peripheral blood neutrophils
(13)
, further supporting a role for B94 in hematopoietic
development. The growth factor-dependent TF1 leukemia cell line
(14)
is permissive for expression of PML-RAR
(15)
, and this cell line was used to identify genes that
are repressed by PML-RAR and induced by RA in a PML-RAR-dependent
manner. In the current report, we show that B94 is one such gene and
provide preliminary evidence that B94 is a potential target for
transcriptional repression by unliganded PML-RAR in APL cells.
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Materials and Methods |
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was from Genzyme (Cambridge, MA), and
antihuman TNF--neutralizing antibody (purified goat IgG) was
purchased from R&D Systems (Minneapolis, MN). Rabbit polyclonal
anti-RAR was from Santa Cruz Biotechnology (Santa Cruz, CA). STAT-60
RNA isolation reagent was purchased from Tel-Test "B" (Friendswood,
TX). The Fast Track Kit for mRNA isolation was obtained from Invitrogen
(Carlsbad, CA). Radioisotope [-32P]dCTP was purchased
from Dupont-New England Nuclear (Wilmington, DE). The human B94 cDNA
expressed sequence tag clone 487045 was obtained from Research Genetics
(Huntsville, AL), and the human RNA Master Blot was purchased from
Clontech (Palo Alto, CA).
Cell Culture and Treatment of Cells.
TF1 parental and TF1-PR cell lines (15)
were cultured in
RPMI 1640 containing 10% FBS and supplemented with granulocyte
macrophage colony-stimulating factor (5 ng/ml), fungizone (1 µg/ml),
and M-plasmocin (10 µg/ml). TF1-PR cells were additionally cultured
in Geneticin at 400 µg/ml. NB4 and K562 cells were cultured in RPMI
1640 supplemented with 10% FBS, penicillin (100 units/ml), and
streptomycin (100 µg/ml). HL-60 and KG-1 cells were grown in
Iscove’s modified Dulbecco’s medium supplemented with 20% FBS,
penicillin (100 units/ml), and streptomycin (100 µg/ml), whereas DAMI
cells were cultured in Iscove’s modified Dulbecco’s medium with 10%
FBS, fungizone (1 µg/ml), and M-plasmocin (10 µg/ml). ATRA was
dissolved in absolute ethanol at 10-3 M and
stored at -20°C for no more than 1 week and used at a final
concentration, 10-6 M. TPA (dissolved in DMSO)
was used at a final concentration of 100 nM.
As2O3 was prepared as a 1 mM stock
solution in PBS for use at a final concentration of 1 µM.
TNF- dissolved in culture medium immediately before use was used at
a final concentration of 200 units/ml. Cycloheximide was dissolved in
H2O and used at 10 µg/ml. Antihuman TNF--neutralizing
antibody (1 mg/ml in PBS) was used at a final concentration of 2
µg/ml. Actinomycin D was dissolved in absolute ethanol and used at 1
µg/ml final concentration. Trichostatin-A was used at a final
concentration of 100 ng/ml.
Clinical Samples.
Samples of blood and fresh and/or cryopreserved bone marrow were
obtained from donors after informed consent under protocols approved by
the Roswell Park Cancer Institute Institutional Review Board. Before
RNA extraction or cryopreservation, mononuclear cells were prepared by
Ficoll-Hypaque density gradient centrifugation. AML cases were
categorized using conventional French-American-British criteria, and
all cases of M3 (APL) were confirmed by cytogenetic and/or
molecular analysis.
RNA Isolation, Northern Blotting, and Microarray Analysis.
Total RNA was isolated using STAT-60 reagent, and polyA mRNA was
isolated using the Fast Track Kit from Invitrogen. Northern blots were
hybridized using ExpressHyb solution (Clontech) according to the
manufacturer’s instructions. A 2.0-kb fragment of chicken ß-actin
was used as a probe to control for the amount of RNA loaded. A 525-bp
B94 cDNA fragment was isolated from 5'-EST clone 487045 after digestion
with EcoRI and NotI and agarose gel purification
using the NucleoTrap Kit (Clontech). The fragment was sequenced in the
Roswell Park Cancer Institute Biopolymer Facility to confirm its
identity with the previously published (10)
human cDNA.
Autoradiography was carried out using Kodak Bio-Max MS Film.
Phosporimaging analysis was performed with a Storm 860 PhosphorImager
(Molecular Dynamics), and densitometry was carried out with a Molecular
Dynamics Computing Densitometer. To prepare cDNA probes for
hybridization to cDNA microarrays, polyA mRNA from treated cells was
isolated and reverse-transcribed in the presence of Cy-5- or
Cy-3-labeled dUTP essentially as described previously
(16)
. Hybridization to microarrays and data acquisition
were performed as reported previously (16)
.
Western Blotting.
Western blot hybridization was performed as described previously
(15)
using rabbit polyclonal anti-RAR (Santa Cruz
Biotechnology).
Construction of PML-RAR Coiled-Coil (
C) Mutant.
Briefly, the PML-RAR L form cDNA was digested with
BSSHII, religated, and cloned into the expression vector
pCINeo (Promega) as described previously (15)
. The
BSSHII fragment removed encompasses amino acids 216–330,
all within PML exon 3, including the distal part of the third zinc
finger, and the first three of four clusters in the coiled-coil domain.
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Results |
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-positive TF1 cells. (TF1-PRL or
TF1-PRS cells), as well as a mutant L form PML-RAR that
contains a deletion of most of the PML coiled-coil domain
(TF1-PRC; Fig. 1
; Ref. 15
). To identify genes specifically induced by RA via PML-RAR, TF1-neo
(control) and TF1-PRL cells were treated with ATRA (1
µM) for 24 h. Poly(A) mRNA was isolated,
reverse-transcribed in the presence of Cy-5- or Cy-3-labeled dUTP, and
hybridized to cDNA microarrays. A full description of the gene
expression profiles obtained will be published
elsewhere.4
One of the genes expressed at a significantly higher level in
ATRA-treated TF1-PRL cells than TF1-neo cells was B94.
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S isoform and the PML-RAR
coiled-coil mutant. As shown in Fig. 2A
, there was no induction of B94 by ATRA in TF1-neo cells or in cells
expressing the mutant PML-RAR protein, but strong induction was
observed in cells expressing either the S or L PML-RAR proteins. The
stronger induction of B94 in TF1-PRS cells may be explained
by the higher amount of PML-RAR protein present in this and all
other S-isoform clones compared with clones expressing the L isoform,
as shown previously (Ref. 15
; Fig. 1B
). The lack of
induction of B94 in TF1-PRC cells was not due to lack of
expression of this mutant protein, as shown in Fig. 1B
. All
TF1 clones, as well as parental TF1 cells, expressed endogenous RAR
(Fig. 1B
; Ref. 15
) and retinoid X receptor (data not
shown). These data indicate that ATRA induction of B94 is mediated by
PML-RAR and is critically dependent on the presence of the
coiled-coil (dimerization) domain of PML. B94 was not induced in TF1-PR
cells by TPA, arsenic trioxide, or the histone deacetylase inhibitor
trichostatin A (data not shown).
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-positive cell lines NB4
and UF1 (Refs. 17, 18
; 2B; data not shown) as well as in
the PML-RAR-negative cell line HL-60 (data not shown). To study the
time course and determine the mechanism of induction of B94 by ATRA,
TF1-PRS cells were treated with ATRA for various times in
the presence or absence of the protein synthesis inhibitor
cycloheximide (Fig. 2C
). Maximum induction of B94 occurred
after 8 h of ATRA treatment, but up-regulation of B94 mRNA was
evident within 1 h of ATRA addition; B94 induction by ATRA was not
blocked by cycloheximide. To determine whether B94 was up-regulated at
the level of transcription, NB4 cells were treated with ATRA in the
presence of the RNA polymerase inhibitor actinomycin D. Actinomycin D
completely abrogated B94 induction (Fig. 2D
), suggesting
that up-regulation of B94 by ATRA is due to a direct effect on
transcription rather than stabilization of its mRNA. B94 regulation was
also assessed during monocytic differentiation in KG-1, TF1, and HL-60
cells, which respond to TPA by differentiation into macrophages.
Treatment of KG-1 and TF1 cells with TPA over a 24-h period failed to
up-regulate B94 (data not shown); however, TPA did induce B94 in HL-60
cells (Ref. 11
; data not shown). Thus, HL-60 cells, which have the
capacity to develop into either neutrophils (with ATRA) or macrophages
(with TPA), expressed increased levels of B94 with either agent. No
increase of B94 was observed in K562 cells induced to undergo erythroid
differentiation with hemin or Adriamycin, or in DAMI cells induced to
undergo megakaryocytic differentiation with TPA (data not shown).
B94 Is Induced Independently by ATRA and TNF- in TF1-PR Cells.
Because B94 was originally identified as a TNF--inducible gene, we
considered the possibility that ATRA induction of B94 was indirect and
mediated by intervening production or secretion of TNF-,
particularly because ATRA has been shown to induce cytokine expression
(including TNF- expression) in hematopoietic cell lines (19
, 20)
. Although the cycloheximide data discussed above suggested
that intervening protein synthesis was not required for B94 induction,
it remained possible that posttranslational mechanisms could have
resulted in increased TNF- secretion. TNF- alone induced B94 gene
expression in TF1-PRS and TF1-neo cells (Fig. 3
) and in NB4 cells (data not shown). This approximately 3-fold induction
was totally abrogated in TF1-neo cells by pretreatment with a
neutralizing anti-TNF- antibody (Fig 3
). The 5-fold induction of B94
by ATRA in TF1-PRS cells was unaffected by addition of the
anti-TNF- antibody (Fig. 3
), proving that intermediary
synthesis/secretion of TNF- was not responsible for induction of the
B94 gene by ATRA in these cells. It is also apparent from Fig. 3
that
the combination of ATRA plus TNF- was at least additive, if not
synergistic, in the induction of B94 in TF1-PRS cells.
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. B94 was expressed in essentially all tissues, but the highest levels
were observed in peripheral blood leukocytes, spleen (fetal and adult),
and lymph node. Substantial expression was also observed fetal kidney,
fetal and adult lung, and placenta. The lowest level of B94 expression
was in the pituitary gland and whole brain tissue (adult and fetal).
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). B94 was highly expressed in normal marrow, chronic myeloid leukemia
marrow, and in marrow from patients with AML subtypes
M0–M2. In contrast, B94 was expressed at much
lower levels in leukemic cells from four patients with APL (Fig. 5A
). This was not due to degradation of RNA in the APL
samples, as shown by the actin control hybridization. Despite its low
level in APL marrow, B94 was induced by ATRA in APL blasts
cultured in vitro (Fig. 5B
).
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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, the oncogene implicated in APL pathogenesis, has been
shown to inhibit myeloid differentiation in the absence (or at low
concentrations) of RA but to facilitate differentiation in the presence
of high concentrations of retinoids (reviewed in Ref. 1
). The mechanism
is presumed to involve repressive and/or inductive effects on
expression of genes involved in myeloid development. At low or
physiological levels of RA, PML-RAR functions as a transcriptional
repressor by recruiting nuclear corepressors and HDACs to the promoter
regions of RA target genes (2
, 4
, 6
, 7)
. The resultant
deacetylation of histones results in a closed chromatin conformation
that is repressive for gene transcription (21)
. High
levels of RA (achieved therapeutically in treatment of APL patients)
result in the release of corepressors from the PML-RAR molecule,
recruitment of transcriptional coactivators, and changes in chromatin
conformation that facilitate gene transcription. Several potential
PML-RAR target genes have been identified, including C/EBP-
(8)
, p21WAF1/CIP1 (9)
, and type
II transglutaminase (22)
. In this report, we provide
evidence that B94 is also a target gene of PML-RAR. In the absence
of RA, this gene is repressed in APL cells (Fig. 5A
) or in
PML-RAR-positive cells (Fig. 3
), whereas it is strongly induced by
ATRA in APL blasts, in cell lines derived from APL patients, and in a
leukemic cell line engineered to express PML-RAR (Figs. 2,
3
, and 5
).
Although the function of the B94 protein is unknown, the tissue
distribution of B94 transcripts supports a role for this molecule in
hematopoiesis. In mice, B94 mRNA is present in many tissues during
embryonic development, including developing vascular structures,
osteoblasts, and liver, but the highest expression of B94 is observed
in hematopoietic and lymphoid tissues (11)
. Its expression
in the liver from 13–17 days post coitus coincides with peak
hematopoietic activity in that organ (11)
. We show here
that B94 mRNA is present at high levels in unfractionated bone marrow
from normal individuals and from patients with myeloid leukemias
(except APL; Fig. 5
). Using in situ hybridization, Wolf
et al. (11)
localized bone marrow expression in
mice to large mononuclear cells, which they interpreted as belonging to
the myelomonocytic lineage. B94 is also expressed during capillary tube
formation in vitro (10)
, and a truncated
transcript was noted in late-stage spermatids (10
, 11)
. In
the current report, B94 mRNA was detectable in many human tissues and
in most hematopoietic cell lines studied, but its expression was
up-regulated by ATRA or phorbol ester only in cells at the promyelocyte
stage of development (HL-60) or in cells that express PML-RAR (NB4,
UF1, and TF1-PR). Our data suggest that the induction of B94 mRNA by
ATRA in these cells occurs primarily at the transcriptional level, and
we hypothesize that the B94 gene promoter will contain a RAR element.
Because B94 is inducible by a variety of stimuli in addition to ATRA,
it will be of some interest to study the promoter of this gene. Study
of the B94 promoter may also provide a model for understanding the
regulation of hematopoietic-specific genes by retinoids and by
PML-RAR.
Although our data and previously published reports (10 , 11) suggest that B94 is involved in hematopoietic development, it is likely to have a broader role in cellular physiology. Over 100 B94-specific expressed sequence tags from diverse organs and tissues have been identified in the Unigene dataset, suggesting that B94 is a widely expressed gene that may play a common role in many different tissues. B94 SAGE tags have also been found in a number of publicly available SAGE libraries,5 particularly in a library constructed from pooled RNA from ovarian carcinoma cell lines, where the frequency of B94 tags was 1010 tags/million. B94 SAGE tags were also found at a high level in several libraries from normal human mammary epithelial cells. The 654-amino acid human B94 protein is an intracellular protein that is homologous (23% amino acid identity; 46% similarity) to rat Sec6 (GenBank accession number U32575), a homologue of a yeast protein (SEC6) that is involved in the Golgi-to plasma membrane stage of the yeast secretory pathway. A human sec6 homologue (GenBank accession number AF055006) has also been identified. Both mature neutrophils and macrophages contain numerous granules that contain proteases and other microbicidal substances, and these granules eventually fuse with either the plasma membrane or with phagosomes to effect killing of pathogenic organisms. Given the homology of B94 with rat and human sec6, it is possible that B94 plays a role in granule or vesicle trafficking within myeloid (and other) cells.
Compared with TF1-PR cells containing intact PML-RAR (S or L
isoform), B94 induction by ATRA was reduced to negligible levels in
TF1-PR cells expressing a mutant PML-RAR construct harboring a
deletion of most of the PML coiled-coil domain( Figs. 1
and 2
). This
region of the PML protein mediates homo- and heterodimerization of PML
and PML-RAR (23)
and is involved in numerous functions
of PML-RAR, including differentiation inhibition (24)
,
transcriptional cooperativity with AP-1 (25)
, and binding
to the retinoblastoma protein (26)
. By interaction with
native PML, PML-RAR is presumed to titrate out and effectively
inactivate PML in APL cells, resulting in aberrant transcriptional
responses in these cells. PML may itself be a transcriptional repressor
(27)
or may modulate transcription indirectly by
interacting with proteins such as cAMP-responsive element binding
protein (28)
and fos (29)
that control
critical transcriptional responses in cells. We hypothesize that lack
of interaction of the mutant PML-RAR with a critical transcriptional
coregulator (PML itself, cAMP-responsive element binding protein, or
fos) explains the loss of B94 induction by ATRA in the
TF1-PRC cells, because a similar PML-RAR coiled-coil
mutant retained DNA binding and transactivation potential in
vitro (24)
.
The induction of B94 by multiple cytokines in addition to ATRA suggests
that it may be involved in a general response of the organism to
inflammation or tissue damage, a speculation supported by the
observation of B94 mRNA induction during angiogenesis (10
, 11)
. ATRA itself induces a number of proinflammatory cytokines,
including IL-8, TNF-, and IL-1ß, in APL cells (30)
,
which suggested that up-regulation of B94 by ATRA in TF1-PR cells could
have been an indirect event, particularly because TNF- also induces
B94 in these cells (Fig. 3
). However, our results indicate that the
induction of B94 by ATRA and the induction of B94 by TNF- are
independent events, thus suggesting distinct mechanisms of
transcriptional activation of the B94 promoter by these two agents.
ATRA and TNF- have been shown to cooperate in activation of the IL-8
promoter via a mechanism that involves nuclear factor 
B
(31)
, and such a mechanism may also be operative in the
case of B94. Ultimately, the role that B94 plays in hematopoiesis will
only become clear with detailed functional studies, including gene
knockout experiments in mice, which are in progress. The currently
available data suggest that the regulation and function of B94 will be
complex, but a compelling case can be made that a full understanding of
its function may provide important insights into both normal and
malignant myelopoiesis.
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Acknowledgments |
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FOOTNOTES |
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1 Supported by NIH Grant CA75049 (to J. L. S.).
D. T. R. is a Walter and Idun Berry Fellow. 
2 To whom requests for reprints should be
addressed, at Department of Medicine, Roswell Park Cancer Institute,
Elm & Carlton Streets, Buffalo, NY 14263. Phone: (716) 845-3544; Fax:
(716) 845-8741; E-mail: James.slack{at}roswellpark.org
3 The abbreviations used are: APL, acute
promyelocytic leukemia; ATRA, all-trans-retinoic acid;
PML-RAR, promyelocytic leukemia-retinoic acid receptor ; RA,
retinoic acid; FBS, fetal bovine serum; TNF, tumor necrosis factor;
poly(A) RNA, polyadenylated RNA; HDAC, histone deacetylase; AML, acute
myelogenous leukemia; TPA,
12-O-tetradecanoylphorbol-13-acetate; SAGE, serial analysis
of gene expression.
4 J. L. Slack, L. Stanley, M. Yu, P. O. Brown,
and D. T. Ross. cDNA microarray analysis of TF1 cells expressing the
APL-specific oncogene PML-RAR, manuscript in preparation.
Received 1/14/00. Accepted 2/18/00.
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  G. Chen, W. Zeng, A. Miyazato, E. Billings, J. P. Maciejewski, S. Kajigaya, E. M. Sloand, and N. S. Young Distinctive gene expression profiles of CD34 cells from patients with myelodysplastic syndrome characterized by specific chromosomal abnormalities Blood, December 15, 2004; 104(13): 4210 - 4218. [Abstract] [Full Text] [PDF]
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D. J. Park, P. T. Vuong, S. de Vos, D. Douer, and H. P. Koeffler Comparative analysis of genes regulated by PML/RAR{alpha} and PLZF/RAR{alpha} in response to retinoic acid using oligonucleotide arrays Blood, November 15, 2003; 102(10): 3727 - 3736. [Abstract] [Full Text] [PDF]
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 J. L. Slack, S. Waxman, G. Tricot, M. S. Tallman, and C. D. Bloomfield Advances in the Management of Acute Promyelocytic Leukemia and Other Hematologic Malignancies with Arsenic Trioxide Oncologist, April 1, 2002; 7(90001): 1 - 13. [Abstract] [Full Text] [PDF]
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 M. H. Einstein, Y. Cruz, M. K. El-Awady, N. C. Popescu, J. A. DiPaolo, M. van Ranst, A. S. Kadish, S. Romney, C. D. Runowicz, and R. D. Burk Utilization of the Human Genome Sequence Localizes Human Papillomavirus Type 16 DNA Integrated into the TNFAIP2 Gene in a Fatal Cervical Cancer from a 39-Year-Old Woman Clin. Cancer Res., February 1, 2002; 8(2): 549 - 554. [Abstract] [Full Text] [PDF]
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 S. Li, D. T. Ross, M. E. Kadin, P. O. Brown, and M. A. Wasik Comparative Genome-Scale Analysis of Gene Expression Profiles in T Cell Lymphoma Cells during Malignant Progression Using a Complementary DNA Microarray Am. J. Pathol., April 1, 2001; 158(4): 1231 - 1237. [Abstract] [Full Text] [PDF]
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